Methotrexate (MTX) is an antimetabolite and immunomodulator that affects many intracellular pathways of purine metabolism. It is effective in reducing the signs and symptoms of rheumatoid arthritis (RA), as well as in slowing or halting radiographic damage. Due to its efficacy, ease of administration and relatively low cost, MTX has become the first-line oral therapy in most patients with RA. In those patients who have an incomplete response to MTX, another DMARD (disease modifying anti-rheumatic drug) is added on top of it. Thus, combination therapy with MTX is more and more frequent in the clinical practice.
Leflunomide is an example of such a DMARD. It was approved in September 1998 for use in RA. It has been shown to reduce the signs and symptoms of the disease, to inhibit structural damage (evidenced by X-ray erosions and joint space narrowing) and to improve physical function. Teriflunomide is the active metabolite of Leflunomide.
Methotrexate is thought to act primarily on purine pathways of cellular metabolism, whereas Leflunomide affects pyrimidine pathways. Given the diverse intracellular pathways affected by both drugs, the combination of Leflunomide and methotrexate has the potential for biochemical synergy. In fact, it has been reported that the combination of both agents led to considerable clinical improvement (see for example, Weinblatt M E et al. “Pharmacokinetics, safety, and efficacy of combination treatment with methotrexate and leflunomide in patients with active rheumatoid arthritis”. Arthritis Rheum 1999; 42 (7): 1322-8 and Kremer J M et al. “Concomitant Leflunomide therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate”. Ann. Intern. Med., 2002; 137, 726-733).
Unfortunately, both methotrexate and leflunomide have serious adverse effects, in particular hepatotoxicity. Methotrexate may cause fatal liver damage such as fibrosis and cirrhosis after prolonged use. Liver enzyme increases are frequently seen during treatment with methotrexate. Hence, regular and careful monitoring of patients taking MTX is essential, particularly when MTX is combined with other DMARDs.
The most common reported adverse events of Leflunomide include diarrhoea, dyspepsia, rash, hair loss, hypertension and elevated hepatic enzymes. The hepatotoxicity potential is of special relevance and regular laboratory tests, including blood tests of liver function, must be performed for all patients taking this medication. Leflunomide is not recommended for use in patients with evidence of hepatitis B or C infection or significant hepatic impairment.
Clinical trials have reported that the number of patients experiencing an increase in liver markers (measured as transaminase levels) is notably higher in the group of Leflunomide plus MTX than in the group of MTX alone. The product information for Leflunomide warns against combination with methotrexate on the basis that such combination therapy can lead to additive or even synergistic hepatotoxicity.
The mechanism responsible for the hepatotoxicity of leflunomide, and in particular of its active metabolite, teriflunomide, is unknown, but it has been attributed to its activity as inhibitor of dihydroorotate dehydrogenase (DHODH). Liver toxicity has thus been identified as an adverse effect directly derived from the mechanism of action of DHODH-inhibitors, which has hampered the development of this class of compounds.